Polymorphism is the ability of a solid material to exist in more than one form or crystal structure. Polymorphism may result from different molecular packing and/or molecular conformations of the molecules of a given compound in the crystal lattice. Polymorphic forms of a given compound have different physical properties, such as solubility, stability, thermal property, morphology of crystals, and mechanical property, etc. One or combination of multiple characterization methods may be used to differentiate the different crystal forms of the same compound, such as X-ray powder diffraction, differential scanning calorimetry, infrared spectroscopy, raman spectroscopy, and solid-state NMR spectroscopy, etc.
New crystalline forms (including anhydrous forms, hydrates and solvates) of the active pharmaceutical ingredients may offer better properties, such as solubility and bioavailability, stability, processability, purification ability. Some new crystalline form may serve as an intermediate crystal form to facilitate solid state transformation to a desired form. Desired new polymorphs can help formulation scientists broaden the choice of crystal forms to optimize the dosage forms.
Dabrafenib is a benzene sulfonamide thiazole compound and is a selective BRAF inhibitor. Results of the Phase I/II clinical trials show Dabrafenib has therapeutical activities and an acceptable safety profile in patients with BRAFV600E-mutan melanoma. The chemical name of Dabrafenib is N-[3-[5-(2-aminopyrimidin-4-yl)-2-(tert-butyl)thiazo-4-lyl]-2-fluoro phenyl]-2,6-difluorobenzenesulfonamide; molecular formula: C23H20F3N5O2S2; formula weight: 519.6; and chemical structural formula as follows:

Patent documents WO2009/137391A2 and U.S. Pat. No. 7,994,185B2 (incorporated into the present application by reference) disclosed identification, preparing process and uses of Dabrafenib. To be specific, example 58a˜c disclosed a number of crystal forms of Dabrafenib and their preparation methods. Wherein, example 58a disclosed a crystal form (hereinafter referred to as the Known Crystal Form 1) and its preparation method. Example 58b and 58c disclosed another crystal form (hereinafter referred to as the Known Crystal Form 2) and its preparation method. Moreover, such patent documents also disclosed that Dabrafenib has the inhibitory effection on one or more Raf-family kinases. The above patent documents mentioned that the Known Crystal Form 1 is crystalline and provided its 1H-NMR data, XRPD pattern and DSC thermogram; the Known Crystal Form 2 was characterized by Raman, XRPD and DSC/TGA analyses to show it is different from the Known Crystal Form 1, but detailed data was not given. The above patent documents did not mention the stability and the conversion relationship of these two crystal forms.
In addition, patent documents WO2012/148588A2 (incorporated into the present application by reference) disclosed a number of crystal forms of Dabrafenib and their preparation methods. Wherein, example 1 disclosed a crystal form (hereinafter referred to as the Known Crystal Form 3) and its preparation method. Furthermore, this patent document provided further characteristic data for the Known Crystal Form 1 and the Known Crystal Form 2 which were previously mentioned in WO2009/137391A2; This patent document provided Raman, XRPD and DSC/TGA analysis data of the Known Crystal Form 1, the Known Crystal Form 2 and the Known Crystal Form 3, but it did not mention the stability and the conversion relationship of these three crystal forms.
Patent document US2012/0196886A1 disclosed a pharmaceutical composition containing Dabrafenib methanesulfonate and use thereof.
In the present research, it was discovered that the Known Crystal Form 1 has the following defects: as an anhydrate, it has about 1.9% of weight change between 20˜80% RH, indicating some hygroscopicity; and it readily converts to other form(s) in water or other water containing system(s), thus unable to maintain its original form.
In the present research, it was discovered that the Known Crystal Form 2 has the following defects: it is unstable; it would convert to other form(s) when exposed to water or other water containing system(s), thus unable to maintain the original form; and after stirring in dichloromethane followed by filtering and drying, it can convert to the Known Crystal Form 1.
In the present research, it was discovered that the Known Crystal Form 3 has the following defects: It is very unstable; it can convert to the Known Crystal Form 1 at room temperature; and it may convert to other form(s) in water or other water containing system(s), thus unable to maintain the original form.
Therefore, there is a need to discover new crystal forms of Dabrafenib with good purity, improved thermodynamical stability at room temperature or in water, and/or little mass change under high humidity conditions, etc., to meet the strict demands for crystal properties in industrial production of pharmaceutical formulations.